Use of the phytocannabinoid cannabidiol (cbd) in combination with a standard anti-epileptic drug (saed) in the treatment of epilepsy

ABSTRACT

The invention relates to the use of cannabidiol (CBD), at a dose of greater than 300 mg/day, in combination with a standard anti-epileptic drug (SAED) which acts via sodium or calcium channels, for use in the treatment of epilepsy. The SAED is preferably one which•modifies low-threshold or transient neuronal calcium currents,or•reduces high-frequency neuronal firing and sodium-dependent action potentials and enhances GABA effects. Preferred SAEDs are ethosuximide and valproate.

This invention relates to the use of the phytocannabinoid cannabidiol(CBD) in combination with a standard anti-epileptic drug (SAED).Preferably the CBD is used in combination with a SAED with a mechanismof action which acts via sodium or calcium channels, more preferably onewhich:

-   -   modifies low-threshold or transient neuronal calcium currents,        as exemplified by ethosuximide; or    -   reduces high-frequency neuronal firing and sodium-dependent        action potentials and may additionally enhance GABA effects, as        exemplified by valproate.

BACKGROUND

Epilepsy is a chronic neurological disorder presenting a wide spectrumof diseases that affect approximately 50 million people worldwide(Sander, 2003). Advances in the understanding of the body's internal‘endocannabinoid’ system has lead to the suggestion that cannabis-basedmedicines may have the potential to treat this disorder ofhyperexcitability in the central nervous system (Mackie, 2006,Wingerchuk, 2004, Alger, 2006).

Cannabis has been ascribed both pro-convulsant (Brust et al., 1992) andanti-convulsant effects. Therefore, it remains to determine whethercannabinoids represent a yet to be unmasked therapeutic anticonvulsantor, conversely, a potential risk factor to recreational and medicinalusers of cannabis (Ferdinand et al., 2005).

In 1975 Consroe et al. described the case of young man whose standardtreatment (phenobarbitol and phenytoin), didn't control his seizures.When he began to smoke cannabis socially he had no seizures. Howeverwhen he took only cannabis the seizures returned. They concluded that‘marihuana may possess an anti-convulsant effect in human epilepsy’.

A study by Ng (1990) involved a larger population of 308 epilepticpatients who had been admitted to hospital after their first seizure.They were compared to a control population of 294 patients who had nothad seizures, and it was found that using cannabis seemed to reduce thelikelihood of having a seizure. However this study was criticized in anInstitute of Medicine report (1999) which claimed it was ‘weak’, as ‘thestudy did not include measures of health status prior to hospitaladmissions and differences in their health status might have influencedtheir drug use’ rather than the other way round.

Three controlled trials have investigated the anti-epilepsy potential ofcannabidiol. In each, cannabidiol was given in oral form to sufferers ofgeneralised grand mal or focal seizures.

Cunha et al (1980) reported a study on 16 grand mal patients who werenot doing well on conventional medication. They received their regularmedication and either 200-300 mg of cannabidiol or a placebo. Of thepatients who received CBD, 3 showed complete improvement, 2 partial, 2minor, while 1 remained unchanged. The only unwanted effect was mildsedation. Of the patients who received the placebo, 1 improved and 7remained unchanged.

Ames (1986) reported a less successful study in which 12 epilepticpatients were given 200-300 mg of cannabidiol per day, in addition tostandard antiepileptic drugs. There seemed to be no significantimprovement in seizure frequency.

Trembly et al (1990) performed an open trial with a single patient whowas given 900-1200 mg of cannabidiol a day for 10 months. Seizurefrequency was markedly reduced in this single patient.

In addition to the disclosures suggesting CBD may be beneficial there isa report (Davis & Ramsey) of tetrahydrocannabinol (THC) beingadministered to 5 institutionalized children who were not responding totheir standard treatment (phenobarbital and phenoytin). One becameentirely free of seizures, one became almost completely free ofseizures, and the other three did no worse than before.

In WO 2006/054057 it is suggested that the cannabinoidTetrahydrocannabivarin (THCV) may behave as anti epileptic, somethingconfirmed by Thomas et al 2005.

In addition WO 2009/007697 describes a THCV and CBD pharmaceuticalformulation. Such a formulation is suggested to be of use in manydifferent types of diseases including epilepsy.

However, there are more than forty recognisable types of epilepticsyndrome partly due to seizure susceptibility varying from patient topatient (McCormick and Contreras, 2001, Lutz, 2004) and a challenge isfinding drugs effective against these differing types.

Neuronal activity is a prerequisite for proper brain function. However,disturbing the excitatory—inhibitory equilibrium of neuronal activitymay induce epileptic seizures. These epileptic seizures can be groupedinto two basic categories:

-   -   a. Partial, and    -   b. Generalised seizures.        Partial seizures originate in specific brain regions and remain        localised—most commonly the temporal lobes (containing the        hippocampus), whereas generalised seizures appear in the entire        forebrain as a secondary generalisation of a partial seizure        (McCormick and Contreras, 2001, Lutz, 2004). This concept of        partial and generalised seizure classification did not become        common practice until the International League Against Epilepsy        published a classification scheme of epileptic seizures in 1969        (Merlis, 1970, Gastaut, 1970, Dreifuss et al., 1981).

The International League Against Epilepsy further classified partialseizures, separating them into simple and complex, depending on thepresence or the impairment of a consciousness state (Dreifuss et al.,1981).

The league also categorized generalised seizures into numerous clinicalseizure types, some examples of which are outlined below:

Absence seizures occur frequently, having a sudden onset andinterruption of ongoing activities. Additionally, speech is slowed orimpeded with seizures lasting only a few seconds (Dreifuss et al.,1981).

Tonic-clonic seizures, often known as “grand mal”, are the mostfrequently encountered of the generalised seizures (Dreifuss et al.,1981). This generalised seizure type has two stages: tonic musclecontractions which then give way to a clonic stage of convulsivemovements. The patient remains unconscious throughout the seizure andfor a variable period of time afterwards.

Atonic seizures, known as “drop attacks”, are the result of sudden lossof muscle tone to either a specific muscle, muscle group or all musclesin the body (Dreifuss et al., 1981).

The onset of epileptic seizures can be life threatening with sufferersalso experiencing long-term health implications (Lutz, 2004). Theseimplications may take many forms:

-   -   mental health problems (e.g. prevention of normal glutamatergic        synapse development in childhood);    -   cognitive deficits (e.g. diminishing ability of neuronal        circuits in the hippocampus to learn and store memories); and    -   morphological changes (e.g. selective loss of neurons in the CA1        and CA3 regions of the hippocampus in patients presenting mesial        temporal lobe epilepsy as a result of excitotoxicity) (Swann,        2004, Avoli et al., 2005)

It is noteworthy that epilepsy also greatly affects the lifestyle of thesufferer—potentially living in fear of consequential injury (e.g. headinjury) resulting from a grand mal seizure or the inability to performdaily tasks or the inability to drive a car unless having had a lengthyseizure-free period (Fisher et al., 2000).

There are many different standard anti-epileptic drugs available at thepresent time including: acetozolamide, carbamazepine, clobazam,clonazepam, ethosuximide, eslicarbazepine acetate, gabapentin,lacosamide, lamotriquine, levetiracetam, oxcarbazepine, Phenobarbital,phenytoin, pregabalin, primidone, rufinamide, sodium valproate,tiagabine, topiramate, valproate, vigabatrin, and zonisamide.

The mode of action of some of these is understood and for others isunknown. Some modes of action are set out in Table 1 below: (Adaptedfrom: Schachter S C. Treatment of seizures. In: Schachter S C, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. SanDiego, Calif.: Academic Press; 1997. p. 61-74)

TABLE 1 Sodium or calcium Antiepileptic drug Mechanism of action channelinvolvement Barbiturates: primidone Enhances GABAergic inhibition(Mysoline), phenobarbital Carbamazepine (Tegretol, Inhibitsvoltage-dependent sodium Sodium Tegretol-XR, Carbatrol) channelsEthosuximide (Zarontin) Modifies low-threshold or transient Calciumneuronal calcium currents Felbamate (Felbatol) Unknown Gabapentin(Neurontin) Unknown Lamotrigine (Lamictal) Inhibits voltage-dependentsodium Sodium channels, resulting in decreased release of the excitatoryneurotransmitters glutamate and aspartate Phenytoin (Dilantin, Phenytek)Blocks sodium-dependent action Sodium/Calcium potentials; reducesneuronal calcium uptake Valproate (Depakote, Depakote Reduceshigh-frequency neuronal Sodium ER, Depakene, valproic acid) firing andsodium-dependent action potentials; enhances GABA effects

Three well-established and extensively used in vivo models of epilepsyare:

-   -   pentylenetetrazole-induced (PTZ) model of generalised seizures        (Obay et al., 2007, Rauca et al., 2004);    -   pilocarpine-induced model of temporal lobe (i.e. hippocampus)        seizures (Pereira et al., 2007); and    -   penicillin-induced model of partial seizures (Bostanci and        Bagirici, 2006).        These provide a range of seizure and epilepsy models, essential        for therapeutic research in humans.

The application WO 02/064109 describes a pharmaceutical formulationwhere the cannabinoids THC and CBD are used. The application goes on tostate that the propyl analogs of these cannabinoids may also be used inthe formulation. Since this application was written it has been shownthat THCV behaves in a very different manner to THC and therefore theassumption that the propyl analogs of cannabinoids behave in a similarmanner to their pentyl counterparts is now not valid.

The application GB0911580.9 describes the use of THCV for the treatmentof generalised seizures, also described is the use of the cannabinoidCBD in combination with the THCV.

It is an object of the present invention to identify novel drugcombinations which will enhance or otherwise offer benefits in the useof SAED's. The use of a combination may allow for lower doses of SAED'sto be used then is conventional.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with a first aspect of the present invention there isprovided cannabidiol, (CBD), at a dose of greater than 300 mg/day, incombination with a standard anti-epileptic drug (SAED) which acts viasodium or calcium channels, for use in the treatment of epilepsy.

The SAED which acts via sodium or calcium channels may be exemplified bya drug which:

-   -   modifies low-threshold or transient neuronal calcium currents,        such as, ethosuximide; or    -   reduces high-frequency neuronal firing and sodium-dependent        action potentials (and may additionally enhance GABA effects),        such as, valproate;        In contrast, a SAED which (solely) enhances GABAergic inhibition        (as opposed to acting via sodium or calcium channels), such as,        phenobarbital, does not appear to provide benefits in        combination with CBD, when tested in a pilocarpine model. Thus,        the selective benefits of CBD with e.g. ethosuximide and        valporate (SAED's with defined and distinct mechanisms of        actions involving calcium and sodium channels) could not be        anticipated.

In accordance with a second aspect of the present invention there isprovided the use of cannabidiol (CBD), at a dose of greater than 300mg/day, in combination with a standard anti-epileptic drug (SAED) whichacts via sodium or calcium channels, in the manufacture of a medicamentfor use in the treatment of epilepsy.

In accordance with a third aspect of the present invention there isprovided a method for the treatment of epilepsy, which comprisesadministering to a subject in need thereof cannabidiol (CBD), at a doseof greater than 300 mg/day, in combination with a standardanti-epileptic drug (SAED) which acts via sodium or calcium channels.

In accordance with a forth aspect of the present invention there isprovided a combination product comprising cannabidiol (CBD), at a doseof greater than 300 mg/day, and a standard anti-epileptic drug (SAED)which acts via sodium or calcium channels.

The respective drugs may be packaged separately with instructions to betaken in combination or may be formulated as a single use product.

Preferably the standard anti-epileptic drug acting via sodium or calciumchannels is taken from the group consisting of: ethosuximide andvalproate.

Preferably the type of epilepsy to be treated is a generalised seizureor a temporal lobe seizure.

The combination may prove beneficial in one or more of the following:

-   -   a. reducing the incidence of tonic-clonic seizures;    -   b. increasing the amount of time a patient is seizure free;    -   c. increasing the latency to onset of seizure;    -   d. decreasing the overall duration of the seizure; and    -   e. reducing the severity and mortality of the seizures.        Thus, the combinations are particularly well suited in the        treatment of conditions generally considered refractory to        existing medication. The combinations would also appear to allow        for the use of lower doses of the SAED's than would be used were        the SAED to be used alone.

In one embodiment the CBD is used with one or more therapeuticallyeffective other phytocannabinoid(s).

Preferably the one or more therapeutically effective otherphytocannabinoid is THCV and/or CBDV.

In one embodiment the CBD is in an isolated form.

In a further embodiment the CBD is in the form of a botanical drugsubstance.

BRIEF DESCRIPTION OF THE DRAWINGS

By way of example only, a number of embodiments of the invention aredescribed hereinafter with reference to the accompanying drawings, inwhich

FIG. 1A-C shows the effect of CBD at 100 mg/kg in combination withvalproate on PTZ-induced seizures;

FIG. 2A-C shows the effect of CBD and valproate on latency, duration andseverity of PTZ-induced seizures;

FIG. 3A-C shows the effect of CBD at 100 mg/kg and ethosuximide onPTZ-induced seizures;

FIG. 4A-C shows the anti-convulsant effects of 100 mg/kg CBD incombination with valproate on the development of pilocarpine-inducedseizures; and

FIG. 5A-C shows the effect of 100 mg/kg CBD in combination withvalproate on the development of pilocarpine-induced seizure andmortality incidence.

Legend to FIG. 1: A: % mortality with (black bars) and without 100 mg/kgCBD (white bars). B: % seizure free with (black bars) and without 100mg/kg CBD (white bars). C: % of animals that developed the most severe(tonic-clonic) seizures with (black bars) and without 100 mg/kg CBD(white bars).

Legend to FIG. 2: A: latency to seizure onset; B: duration of seizureactivity of those animals that survived; C: median seizure severity.

Legend to FIG. 3: A: latency to onset of seizures at different doses ofethosuximide without (black) or with (grey unfilled) 100 mg/kg CBD. B:Seizure severity. C: Percentage mortalities, key as in A.

Legend to FIG. 4: Mean latency to onset (A), development of bilateralseizures (B) and tonic-clonic seizures (C).

Legend to FIG. 5: A: Proportion (%) of animals in each dose group thatexhibited fully developed tonic-clonic seizures. B: Proportion (%) ofanimals in each dose group that died. C: Proportion (%) of animals ineach dose group that were seizure free.

DETAILED DESCRIPTION

The examples below describe the use of isolated CBD in combination withstandard anti-epileptic drugs (SAEDs) in two different models ofepilepsy, namely the PTZ-induced seizure model and thepilocarpine-induced seizure model. The SAEDs used in these examples areethosuximide, valproate and Phenobarbital (Pilocarpine model only). Itis important to note that there are many different SAEDs available andthe drugs chosen for these experiments provide a general overview of howthe phytocannabinoid CBD is able to work in combination with differentclasses of drugs used in the treatment of epilepsy.

EXAMPLE 1

The Use of the Phytocannabinoid CBD in Combination with a StandardAnti-Epileptic Drug (SAED) in the PTZ-Model of Epilepsy

Methodology: Animals:

Male Wistar rats (P24-29; 75-110 g) were used to assess the effects ofthe phytocannabinoid CBD in combination with SAEDs in the PTZ model ofgeneralised seizures. Animals were habituated to the test environment,cages, injection protocol and handling prior to experimentation. Animalswere housed in a room at 21° C. on a 12 hour light: dark cycle (lightson 0900) in 50% humidity, with free access to food and water.

The human dose equivalent (HED) can be estimated using the followingformula:

${HED} = {{Animal}\mspace{14mu} {dose}\mspace{14mu} \left( {{mg}\text{/}{kg}} \right)\mspace{14mu} {multiplied}\mspace{14mu} {by}\mspace{14mu} \frac{{Animal}\mspace{14mu} K_{m}}{{Human}\mspace{14mu} K_{m}}}$

-   The K_(m) for a rat is 6 and the K_(m) for a human is 37.    Thus, for a human of approx 60 Kg a 100 mg/Kg dose in rat would    equate to a human dose of about 1000 mg. Human doses of greater than    300 mg/day, through 400 mg/day in 100 mg intervals (namely through    500, 600, 700, 800, 900, 1000, 1100, 1200, 1300 and 1400 mg) to as    much as 2000 mg/day are envisaged based on dose escalating studies    with CBD (Example 2).

Experimental Setup:

Five 6 L Perspex tanks with lids were placed on a single bench withdividers between them. Closed-circuit television (CCTV) cameras weremounted onto the dividers to observe rat behaviour. Sony Topica CCDcameras (Bluecherry, USA) were linked via BNC cables to a low-noise PCvia Brooktree digital capture cards (Bluecherry, USA). Zoneminder(http://www.zoneminder.com) software was used to monitor rats, start andend recordings and manage video files. In-house Linux scripts were usedto encode video files into a suitable format for further offlineanalysis using The Observer (Noldus Technologies).

PTZ Model:

A range of doses of PTZ (50-100 mg/kg body weight) were used todetermine the best dose for induction of seizures (data not shown). As aresult, a dose of 80 mg/kg injected intra-peritoneally (IP; stocksolution 50mg/ml in 0.9% saline) were used to screen the CBD/SAEDscombinations.

Experimental Protocols:

On the day of testing, isolated CBD was administered viaintra-peritoneal (i.p.) injection at a dose of 100 mg/kg alongsideanimals that were injected with a matched volume of the cannabinoidvehicle (2:1:17 ethanol:Cremophor:0.9% w/v NaCl solution), which servedas the negative control group. Animals were then observed for 1 hour,after which time they received an IP injection of 80 mg/kg PTZ. Negativevehicle controls were performed in parallel with cannabinoid-dosedsubjects. After receiving a dose of PTZ, animals were observed andvideoed to determine the severity of seizure and latency to severalseizure behaviour types (see in vivo analysis, below). Animals werefilmed for half an hour after last sign of seizure, and then returned totheir cage.

In Vivo Analysis:

Animals were observed during experimental procedures, but all analysiswas performed offline on recorded video files using The Observerbehavioural analysis software (Noldus, Netherlands). A seizure severityscoring system was used to determine the levels of seizure experiencedby subjects (Pohl & Mares, 1987). All signs of seizure were detailed forall animals.

TABLE 1.1 Seizure severity scoring scale, adapted from Pohl & Mares,1987. Seizure Righting score Behavioural expression reflex 0 No changesto behaviour Preserved 0.5 Abnormal behaviour (sniffing, excessivewashing, Preserved orientation) 1 Isolated myoclonic jerks Preserved 2Atypical clonic seizure Preserved 3 Fully developed bilateral forelimbclonus Preserved 3.5 Forelimb clonus with tonic component and bodyPreserved twist 4 Tonic-clonic seizure with suppressed tonic phase Lost5 Fully developed tonic-clonic seizure Lost 6 DeathLatency from Injection of PTZ to Specific Indicators of SeizureDevelopment:

The latency (in seconds) from injection of PTZ to first myoclonic jerk(FMJ; score of 1), and to the animal attaining “forelimb clonus withtonic component and body twist” (score of 3.5) were recorded. FMJ is anindicator of the onset of seizure activity, whilst >90% of animalsdeveloped scores of 3.5, and so is a good marker of the development ofmore severe seizures. Data are presented as the mean±S.E.M. within anexperimental group.

Maximum Seizure Severity:

This is given as the median value for each experimental group based onthe scoring scale below.

Percentage Mortality:

The percentage of animals within an experimental group that died as aresult of PTZ-induced seizures. Note that the majority of animals thatdeveloped tonic-clonic seizures (scores of 4 and 5) died as a result,and that a score of 6 (death) automatically denotes that the animal alsoexperienced tonic-clonic seizures.

Seizure Duration:

The time (in seconds) from the first sign of seizure (typically FMJ) toeither the last sign of seizure or, in the case of subjects that died,the time of death—separated into animals that survived and those thatdid not. This is given as the mean±S.E.M. for each experimental group.

Statistics:

For measures of latency and severity, one way analysis of variance(ANOVA) was performed on the test groups to detect overall combinationaleffects of CBD and SAEDs (p≦0.05 considered significant).

Significant ANOVA results were followed by post hoc tests to testdifferences between vehicle and drug groups (Tukey's test, p≦0.05considered significant).

Results:

From FIG. 1 it can be seen that the addition of CBD to the SAEDvalproate has an effect on reducing the percentage mortality and theincidence of tonic-clonic seizures. It is also shown that thecombination of CBD and the higher dose of valproate is more effective atincreasing the amount of time that the animal was seizure free.

FIG. 2 demonstrates that the combination of CBD and valproate was ableto increase the latency to onset of seizure at all dose ranges, inaddition it decreased the overall duration of the seizure.

The data shown in FIG. 3 demonstrates that the combination of CBD withthe SAED ethosuximide was also effective at reducing the severity andmortality of the seizures. It also at the higher dose of ethosuximidewas able to increase the latency to onset of the seizures.

Conclusion:

The data demonstrated in this Example clearly shows that the combinationof CBD with a SAED which has a mechanism of action involving sodium orcalcium channels is of value when treating generalised seizures.

EXAMPLE 2

The Use of the Phytocannabinoid CBD in Combination with a StandardAnti-Epileptic Drug (SAED) in the Pilocarpine Model of (Temporal Lobe)Epilepsy

Methodology:

Isolated CBD was injected intra-peritoneally (IP) in the standardvehicle (1:1:18 ethanol:Cremophor:0.9% ^(w)/_(v) NaCl) at doses of 50,100 and 200 mg/kg alongside animals that received vehicle alone at amatched volume. 15 minutes later methylscopolamine (1 mg/kg; to reduceperipheral muscarinic effects of pilocarpine) was administered followed,45 minutes later by pilocarpine (380 mg/kg, IP) administration.

Results:

FIG. 4 demonstrates the anti-convulsant effects of a combination of CBDand valproate in the pilocarpine model of epilepsy. These data show thatthe combination of the CBD and valproate was able to increase thelatency of onset of the seizure.

It can be seen from the data illustrated in FIG. 5 that in addition toincreasing the latency of onset of the seizure the combination of CBDand valproate was able to decrease mortality and the percentage oftonic-clonic seizures.

Table 2.1 below describes the data in more detail.

TABLE 2.1 Anti-convulsant effects of CBD and valproate in thepilocarpine model of epilepsy CBD in Combination Val- with CBD proateValproate Seizure Measure Effects Effects Effects ALL Mean number of **# EPISODES episodes Mean time spent in * episodes Mean duration of *episodes Mean severity of * ** episodes Percentage ≧3 episodes #Percentage episode free ** EPISODE 1 Latency ** Duration Severity *EPISODE 2 Latency # Duration # Severity * Key: # = p < 0.01; * = p <0.05; ** = p < 0.01

The table above clearly shows some of the advantages of using acombination of the two compounds.

Table 2.2 below describes the effect of using the phytocannabinoid CBDin combination with yet a further SAED, phenobarbital, in thepilocarpine model of epilepsy.

TABLE 2.2 Effects of CBD and phenobarbital on the pilocarpine model ofepilepsy CBD Phenobarbitol (mg/kg) (mg/kg) Seizure free (%) Onsetlatency (s) 0 0 0 750 100 0 0 500 0 10 25 800 100 10 25 750 0 20 55 900100 20 55 930 0 40 75 1800 100 40 85 900

In contrast to the valproate combination data, this result demonstratethe selective nature of the combinations which is likely attributed tothe different mechanisms of actions of these SAED's.

Overall Conclusion:

The data demonstrated in the above Examples shows that the combinationof CBD with standard anti-epileptic drugs acting via sodium or calciumchannels may be beneficial in the treatment of different types ofepilepsy. This finding is of great significance to the many epilepsysufferers whose condition is refractory to existing medication.

1. A method for treating epilepsy comprising administering to a subject in need thereof cannabidiol (CBD), at a dose of greater than 300 mg/day, in combination with a standard anti-epileptic drug (SAED) which acts via sodium or calcium channels.
 2. (canceled)
 3. The method of claim 1, wherein the SAED is a drug which: modifies low-threshold or transient neuronal calcium currents, or reduces high-frequency neuronal firing and sodium-dependent action potentials and enhances GABA effects.
 4. The method of claim 1, wherein the SAED is selected from the group consisting of: ethosuximide and valproate.
 5. The method of claim 1, wherein the type of epilepsy to be treated is generalised seizure or temporal lobe seizure.
 6. The method of claim 1, wherein the type of epilepsy to be treated is refractory to existing medication.
 7. The method of claim 1, wherein the CBD is used with one or more other therapeutically effective phytocannabinoids.
 8. The method of claim 7, wherein the one or more other therapeutically effective phytocannabinoid is THCV and/or CBDV.
 9. The method of claim 1, wherein the CBD is an isolated phytocannabinoid.
 10. The method of claim 1, wherein the CBD is in the form of a botanical drug substance.
 11. (canceled)
 12. A combination product comprising cannabidiol (CBD), at a dose of greater than 300 mg/day, and a standard anti-epileptic drug (SAED) which acts via sodium or calcium channels. 